Intensive research into the etiology of age-related diseases and the diagnosis and pharmacological treatment of elderly patients is essential to solve the urgent medical problems facing our society today. Neuropharmacological studies of brains from senescent laboratory animals are especially appropriate to an investigation of the aging process. Since clinical depression is the most common psychological disorder among elderly patients and its treatment with antidepressant drugs may depend upon a pharmacological regulation of central 5-HT2 receptors, this study is designed to assess biochemical and behavioral parameters of 5-HT2 receptor function in aged mice after chronic antidepressant administration. The main objective of this proposal is to assay serotonin-2 (5-HT2) receptors in 3,10 and 27 month old mice, following chronic treatment with amitryptaline, desipramine or iprindole by (i) direct biochemical quantitation of 5-HT2 receptor number and affinity using the 3H-ketanserin (3H-K) radioreceptor binding assay; (ii) measuring the in vitro interaction of 5-HT agonists and antagonists at 3H-K binding sites; and (iii) determining the behavioral sensitivity of central 5-HT systems using the mescaline-induced head-twitching test. Possible age-related differences in the disposition of antidepressant drugs will also be studied using HPLC methods to determine brain and plasma levels of these drugs following a 3-week treatment regimen. Hence, both pharmacodynamic measures of 5-HT2 receptor function and pharmacolinetic parameters of antidepressant drug disposition will be compared in young, adult and senescent mice. The long-term aim of these studies is to investigate neurotransmitter receptor plasticity, and therefore neuronal communication and pharmacological mechanisms, as a function of advanced age. The experiments described here will characterize the effects of a clinically relevant class of psychotherapeutic drugs on a well-defined population of CNS receptors. Ultimate goal of such research is to improve the diagnosis and treatment of elderly patients afflicted with clinical depression, as well as other psychological and neurological disorders associated with advanced age.